Tertiary 2-haloethylamine derivatives of the muscarinic agent McN-A-343, [4-[[N-(3-chlorophenyl)carbamoyl]oxy]-2-butynyl]trimethylammonium chloride.
4-[(2-Chloroethyl)methylamino]-2-butynyl N-(3-chlorophenyl)carbamate (2) and 4-[(2-bromoethyl)methylamino]-2-butynyl N-(3-chlorophenyl)carbamate (3) were synthesized. Compounds 2 and 3 cyclized at neutral pH to an aziridinium ion (4). The rate constants for the cyclization of 2 and 3 at 37 degrees C were about 0.01 and 0.4 min-1, respectively, as measured by titrimetric analysis and by 1H NMR spectroscopy. The aziridinium ion had 1/4 the potency of McN-A-343 (1) as a ganglionic muscarinic stimulant in the anesthetized, pentolinium-treated rat but showed no muscarinic effects on the isolated guinea pig ileum. It caused alkylation of muscarinic receptors in homogenates of the rat cerebral cortex. An irreversible blockade of central muscarinic receptors was also observed after intravenous administration of 3 to mice. Because of its selectivity, irreversible actions, and ability to pass into the central nervous system, 3 should become a valuable tool in studies of muscarinic receptors.
Ringdahl
B
B
Department of Pharmacology, School of Medicine, University of California, Los Angeles 90024-1735.
Mellin
C
C
Ehlert
F J
FJ
Roch
M
M
Rice
K M
KM
Jenden
D J
DJ
D000478:Alkylation; D000480:Alkynes / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002219:Carbamates / Q000138:chemical synthesis / Q000494:pharmacology*; D055598:Chemical Phenomena; D002621:Chemistry; D003500:Cyclization; D006168:Guinea Pigs; D007082:Ileum / Q000502:physiology; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D012044:Regression Analysis
D000480:Alkynes; D002219:Carbamates; D011976:Receptors, Muscarinic; C062453:BR 383; C062452:BR 384; D011813:Quinuclidinyl Benzilate